The National Institute of Mental Health (NIMH), the
National Institute on Aging (NIA), and the National Institute of Neurological
Disorders and Stroke (NINDS) invite research grant applications focused on
elucidating the mechanisms of HIV-associated neuropathogenesis in the context
of aging, chronic infection with HIV, and long term exposure to Highly Active
Antiretroviral Therapy (HAART). The neuropathogenic mechanisms of
HIV-Associated Neurocognitive Disorders (HAND) may be distinct in the aging
HIV-infected populations given the potential interactions between aging
associated events, HIV-associated neurodegenerative processes, and exposure
to HAART. Understanding the pathogenesis of HAND in HIV-infected individuals
over 50 years of age, in light of potential interactions with HAART,
neurodegenerative diseases, and aging-related co-morbid conditions are the
focus of this announcement. Applications ranging from basic research to
clinical diagnosis and treatment in domestic and international settings are
of interest. Multidisciplinary research teams and collaborative alliances are
encouraged, but not required.

Key Dates

Posted Date

April 6, 2011

Open Date (Earliest Submission Date)

August 9, 2011

Letter of Intent Due Date

August 9, 2011

Application Due Date(s)

September 9, 2011

Scientific Merit Review

October 2011

Advisory Council Review

January 2012

Earliest Start Date(s)

April 2012

Expiration Date

September 10, 2011

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in
the SF
424 (R&R) Application Guide except where instructed to do otherwise (in
this FOA or in a Notice from the NIH Guide for Grants and Contracts).
Conformance to all requirements (both in the Application Guide and the FOA)
is required and strictly enforced. Applicants must read and follow all
application instructions in the Application Guide as well as any
program-specific instructions noted in Section
IV. When the program-specific instructions deviate from those in the
Application Guide, follow the program-specific instructions. Applications that
do not comply with these instructions may be delayed or not accepted for review.

The National Institute of Mental Health (NIMH), the National
Institute on Aging (NIA), and the National Institute of Neurological Disorders
and Stroke (NINDS) invite research grant applications focused on elucidating
the mechanisms of HIV-associated neuropathogenesis in the context of aging,
chronic infection with HIV, and long term exposure to Highly Active
Antiretroviral Therapy (HAART). The neuropathogenic mechanisms of
HIV-Associated Neurocognitive Disorders (HAND) may be distinct in the aging
HIV-infected populations given the potential interactions between aging
associated events, HIV-associated neurodegenerative processes, and exposure to
HAART. Understanding the pathogenesis of HAND in HIV-infected individuals over
50 years of age, in light of potential interactions with HAART,
neurodegenerative diseases, and aging-related co-morbid conditions are the
focus of this announcement. Applications ranging from basic research to
clinical diagnosis and treatment in domestic and international settings are of
interest. Multidisciplinary research teams and collaborative alliances are
encouraged, but not required.

Background

A major age-related demographic shift in HIV-infected
patients has been noted by clinicians and documented by the Center for Disease
Control (CDC). The CDC projects that by 2015, more than half of all
HIV-infected individuals in the United States will be over the age of 50.
During the next decade, a rapid increase in HIV prevalence among the elderly is
expected to derive from two subpopulations: (1) HIV-diagnosed cases of a
“younger group” surviving into older age because of the efficacy of HAART in
reducing mortality; and (2) newly HIV-infected cases of an “older group”.
Coupled with the aging process, the extended exposure of these adults to both
HIV and antiretroviral drugs appears to increase their risk of illness and
death from cardiovascular, bone, kidney, liver, lung, neurologic and
neuropsychiatric complications. While all of these complications impact
HIV-infected aging populations the focus of this announcement is to stimulate
research on the pathophysiology and treatment of HAND in HIV-infected people
over 50 years of age who are on HAART.

The prevalence of HAND remains high despite wide spread use
of anti-retroviral therapy. A recently completed large epidemiologic study by
the CHARTER (CNS HIV
Anti-retroviral Effects Research) group examined 1,574 participants
cross-sectionally and 657 participants longitudinally and has reported a HAND
prevalence rate of greater than 50% in HIV infected individuals in the United
States. Recent studies are showing that the phenotype of neurologic and
neurocognitive complications are evolving in the era of HAART. In an effort to
accurately classify the phenotypic changes seen in the HAART era, a revised
American Academy of Neurology definitional criteria for HAND was adopted. The
categories of HAND include Asymptomatic Neurocognitive Impairment (ANI), Mild
Neurocognitive Disorder (MND), and HIV-Associated Dementia (HAD). In the
current treatment environment, MND is the most prevalent form of HAND; yet even
mild neurocognitive deficits can interfere with activities of daily living and
reduce the quality of life in long-standing aviremic HIV-positive patients.

The pathophysiology of HAND may be distinct in older
HIV-infected patients given the potential interactions between HIV-associated
neurodegenerative processes, long term HAART, and aging-associated events.
HIV-involvement of the brain has traditionally been classified as a subcortical
dementia with productive infection of perivascular macrophages, microglia, and
restrictive infection of astrocytes, but not neurons. Recent research suggests
that both cortical and subcortical areas of the brain are affected by HIV in
the HAART era. Additionally, functional MRI scans, which link neural activity
levels to measured changes in cerebral blood flow and oxygenation in the brain,
found HIV-positive subjects to be functionally equivalent to HIV-negative
patients who were 15–20 years older. Long term HAART has been associated with
increased neuronal toxicity and has been shown to exacerbate cerebrovascular
disease resulting from hypercholesterolemia and diabetes. Coincident with the
introduction of HAART, the rate of hospitalization due to ischemic stroke in HIV-infected
patients rose by 67% between 1997 and 2006. As HIV-infected patients are
growing older, adverse effects of HAART and drug-drug interactions with
aging-related diseases and medications become relatively more important. Given
the potential for synergy between HIV and aging, further research to determine
whether HIV-related injury to the brain continues to accrue in some patients is
needed.

There is a growing body of research indicating overlapping
neuropathologic features between aging-associated neurodegenerative disease and
HAND. Although the brain pathology differs between HAND and Alzheimer’s
disease, HIV-positive brains derived from patients over 50 years of age have
been shown to accumulate abnormal proteins including amyloid, alpha-synuclein,
and hyper-phosphorylated tau. Measurements of ß-Amyloid (1-42) in the CSF
of cognitively impaired patients with HIV were noted to be similar to those in
patients with mild dementia of the Alzheimer type. The mechanism of HIV induced
dysregulation of amyloid expression is an area of considerable research. For
example, HIV Tat protein has been shown to inhibit neprilysin; a neuronal
amyloid-beta degrading enzyme. Other studies have examined the impact of HIV on
control of amyloid-beta production, solubility and clearance. Additional
research to further define mechanisms of HIV-induced dysregulation of protein
clearance and impact on neurodegenerative processes is needed.

The role of host genetic factors in determining
susceptibility of the aging to HAND is also of interest for this initiative.
Epidemiological data from the Hawaii Aging with HIV cohort demonstrated an
association between the genetic apolipoprotein-epsilon4 allele, APOE-E4, and
dementia among older, but not among younger HIV-1-infected patients. Other investigators
have examined the relationship between cerebrospinal fluid apolipoprotein E
(APOE) levels, the expression of various APOE alleles and cognitive impairment.
Their research suggests that the relatively higher levels of CSF APOE in E4+
HIV+ (having APOE-E4 isoforms) may negatively impact the brain and lead to
poorer cognitive outcomes, while those individuals without the E4 allele (with
APOE-E2 and APOE-E3 isoforms) may show compensatory responses that lead to
better cognitive performance. These initial studies have yielded valuable data
and further research is needed to identify other host genetic factors that may
predict the CNS metabolic, vascular, and neurobiological events that impact
neurocognitive outcomes in aging HIV-infected individuals.

A variety of immunologic factors may also contribute to
neurodegenerative processes in aging HIV-infected individuals. For example, the
continued prevalence of cognitive impairment despite good virologic control in
the era of HAART may be due to a “legacy effect” resulting from a history of
advanced immunosuppression accompanied by high plasma viral load and low CD4
nadir. Age-associated declines in immune function, termed immunosenescence, may
also impact HAND in the over 50 HIV-positive population. Senescence of T cells
is normal given that production of naïve T lymphocytes by the thymus is reduced
after the age of 50. Aging and chronic HIV-infection are both associated with
activation of the immune system, increased levels of circulating inflammatory
mediators, and inflammation which may have a significant impact on
HIV-associated CNS disease.

In summary, the goal of this announcement is to define and
elucidate novel mechanisms of pathogenesis that are driving neurocognitive
decline at the intersection of HIV-associated neurodegenerative processes,
aging associated CNS disease, chronic HAART treatment effects, and host
susceptibility factors. The ultimate goal of this initiative is to help develop
novel strategies for treatment of neurocognitive impairment in the HIV positive
aging population.

Areas of Research Interest

The research areas that are pertinent to this FOA include,
but are not limited to, the items listed below:

Appraise the pathogenic mechanisms and cell & molecular basis
of HIV-associated neurocognitive dysfunction in the over 50 HIV-infected
population;

Investigate aspects of HIV infection that uniquely influence the
aging nervous system and impact on the neurocognitive dysfunction in the over
50 HIV-infected population;

Examine the contribution of CNS inflammation and persistent
immunodeficiency resulting from aging associated immunosenescence to the
pathogenesis of HIV-induced neurocognitive dysfunction in the over 50
HIV-infected population;

Identify and validate biomarkers that provide insight into the pathogenesis
of HAND in the aging HIV-infected population, or aid in distinguishing HAND
from other aging-related neurocognitive disorders (For example; neopterin, Abeta42,
APOE4, tau, phospho-tau, and metabolic biomarkers associated with impaired
blood flow to the brain);

Applicant organizations must complete the following registrations
as described in the SF 424 (R&R) Application Guide to be eligible to apply
for or receive an award. Applicants must have a valid Dun and Bradstreet
Universal Numbering System (DUNS) number in order to begin each of the following
registrations.

All Program Directors/Principal Investigators (PD/PIs) must
also work with their institutional officials to register with the eRA Commons
or ensure their existing eRA Commons account is affiliated with the eRA Commons
account of the applicant organization.

All registrations must be completed by the application due date. Applicant
organizations are strongly encouraged to start the registration process at
least four (4) weeks prior to the application due date.

Eligible Individuals (Program Director/Principal
Investigator)

Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Program Director/Principal
Investigator (PD/PI) is invited to work with his/her organization to develop an
application for support. Individuals from underrepresented racial and ethnic
groups as well as individuals with disabilities are always encouraged to apply
for NIH support.

Applicant organizations may submit more than one application,
provided that each application is scientifically distinct.

Section IV. Application and Submission Information

1. Requesting an Application
Package

Applicants must download the SF424 (R&R) application
package associated with this funding opportunity using the “Apply for Grant
Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in
the SF424
(R&R) Application Guide, except where instructed in this funding
opportunity announcement to do otherwise. Conformance to the requirements in
the Application Guide is required and strictly enforced. Applications that are
out of compliance with these instructions may be delayed or not accepted for
review.

Letter of Intent

Although a letter of intent is not required, is not binding,
and does not enter into the review of a subsequent application, the information
that it contains allows IC staff to estimate the potential review workload and
plan the review.

By the date listed in Part 1. Overview
Information, prospective applicants are asked to submit a letter of intent
that includes the following information:

Descriptive title of proposed research
Name, address, and telephone number of the PD(s)/PI(s)
Names of other key personnel
Participating institutions
Number and title of this funding opportunity

The forms package associated with this FOA includes all
applicable components, mandatory and optional. Please note that some
components marked optional in the application package are required for
application submission. Follow all instructions in the SF424 (R&R)
Application Guide to ensure you complete all appropriate “optional” components.

Page Limitations

All page limitations described in the SF424 Application
Guide and the Table of
Page Limits must be followed.

PHS 398 Research Plan Component

All instructions in the SF424 (R&R) Application Guide
must be followed, with the following additional instructions:

Resource Sharing Plan

Individuals are required to comply with the
instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model
Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424
(R&R) Application Guide, with the following modifications:

All applications, regardless of the amount of direct costs requested
for any one year, should address a Data Sharing Plan.

Appendix

Do not use the appendix to circumvent page limits. Follow
all instructions for the Appendix as described in the SF424 (R&R)
Application Guide.

Foreign Organizations

Foreign (non-US) organizations must follow policies
described in the NIH Grants
Policy Statement, and procedures for foreign organizations described
throughout the SF424 (R&R) Application Guide.

3. Submission Dates and
Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in
advance of the deadline to ensure they have time to make any application
corrections that might be necessary for successful submission.

Organizations must submit applications via Grants.gov, the online portal to find and apply for grants
across all Federal agencies. Applicants must then complete the submission
process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

Applicants
are responsible for viewing their application in the eRA Commons to ensure accurate
and successful submission.

Information on the submission process and a definition of
on-time submission are provided in the SF424 (R&R) Application Guide.

For assistance with your electronic application or for more information on the electronic submission
process, visit Applying
Electronically.

Important
reminders:All PD/PIs must include their eRA Commons ID in the Credential
fieldof the Senior/Key Person Profile Component of the SF 424(R&R) Application
Package. Failure to register in the Commons and to include a valid PD/PI
Commons ID in the credential field will prevent the successful submission of an
electronic application to NIH.

The applicant organization must ensure that the DUNS number it provides on the
application is the same number used in the organization’s profile in the eRA
Commons and for the Central Contractor Registration (CCR). Additional
information may be found in the SF424 (R&R) Application Guide.

Upon receipt, applications will be evaluated for
completeness by the Center for Scientific Review and responsiveness by components of participating organizations,
NIH. Applications that are incomplete and/or nonresponsive will not be
reviewed.

In order to expedite review, applicants are requested to
notify the NIMH Referral Office by email at nimhreferral@mail.nih.gov when the
application has been submitted. Please include the FOA number and title, PD/PI
name, and title of the application.

Applicants are required to follow the instructions for
post-submission materials, as described in NOT-OD-10-115.

Section V. Application Review Information

1.
Criteria

Only the review criteria described below will be considered
in the review process. As part of the NIH mission,
all applications submitted to the NIH in support of biomedical and behavioral
research are evaluated for scientific and technical merit through the NIH peer
review system.

Overall Impact

Reviewers will provide an overall impact/priority score to
reflect their assessment of the likelihood for the project to exert a
sustained, powerful influence on the research field(s) involved, in
consideration of the following review criteria and additional review criteria
(as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in
the determination of scientific merit, and give a separate score for each. An
application does not need to be strong in all categories to be judged likely to
have major scientific impact. For example, a project that by its nature is not
innovative may be essential to advance a field.

Significance

Does the project address an important problem or a
critical barrier to progress in the field? If the aims of the project are
achieved, how will scientific knowledge, technical capability, and/or clinical
practice be improved? How will successful completion of the aims change the
concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field? Does the project have the potential to
lead to further understanding of HIV neuropathogenesis, progression, or clinical
manifestation of HAND in HIV-infected people over the age of 50 years?

Investigator(s)

Are the PD/PIs, collaborators, and other researchers
well suited to the project? If Early Stage Investigators or New Investigators,
or in the early stages of independent careers, do they have appropriate
experience and training? If established, have they demonstrated an ongoing
record of accomplishments that have advanced their field(s)? If the project is
collaborative or multi-PD/PI, do the investigators have complementary and
integrated expertise; are their leadership approach, governance and
organizational structure appropriate for the project?

Innovation

Does the application challenge and seek to shift
current research or clinical practice paradigms by utilizing novel theoretical
concepts, approaches or methodologies, instrumentation, or interventions? Are
the concepts, approaches or methodologies, instrumentation, or interventions
novel to one field of research or novel in a broad sense? Is a refinement, improvement,
or new application of theoretical concepts, approaches or methodologies,
instrumentation, or interventions proposed? Does this project have the potential to discover novel neuropathogenic paradigms to account for
potential interactions between the virus and aging-related disorders in the
CNS?

Approach

Are the overall strategy, methodology, and analyses
well-reasoned and appropriate to accomplish the specific aims of the project?
Are potential problems, alternative strategies, and benchmarks for success
presented? If the project is in the early stages of development, will the
strategy establish feasibility and will particularly risky aspects be
managed?

If the project involves clinical research, are the plans for 1) protection of
human subjects from research risks, and 2) inclusion of minorities and members
of both sexes/genders, as well as the inclusion of children, justified in terms
of the scientific goals and research strategy proposed? Does the proposal for identification of aging related effects of HIV in the CNS include an idea of how
one would validate their influence with respect to the pathophysiology of HAND?

Environment

Will the scientific environment in which the work
will be done contribute to the probability of success? Are the institutional
support, equipment and other physical resources available to the investigators
adequate for the project proposed? Will the project benefit from unique
features of the scientific environment, subject populations, or collaborative
arrangements?

Additional Review Criteria

As applicable for the project proposed, reviewers will
evaluate the following additional items while determining scientific and
technical merit, and in providing an overall impact/priority score, but will
not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or
more of the six categories of research that are exempt under 45 CFR Part 46, the
committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials. For
additional information on review of the Human Subjects section, please refer to
the Human
Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and
Children

When the proposed project involves clinical research,
the committee will evaluate the proposed plans for inclusion of minorities and
members of both genders, as well as the inclusion of children. For additional
information on review of the Inclusion section, please refer to the Human
Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live
vertebrate animals as part of the scientific assessment according to the
following five points: 1) proposed use of the animals, and species, strains,
ages, sex, and numbers to be used; 2) justifications for the use of animals and
for the appropriateness of the species and numbers proposed; 3) adequacy of
veterinary care; 4) procedures for limiting discomfort, distress, pain and
injury to that which is unavoidable in the conduct of scientifically sound
research including the use of analgesic, anesthetic, and tranquilizing drugs
and/or comfortable restraining devices; and 5) methods of euthanasia and reason
for selection if not consistent with the AVMA Guidelines on Euthanasia. For
additional information on review of the Vertebrate Animals section, please
refer to the Worksheet
for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures
proposed are potentially hazardous to research personnel and/or the
environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

Additional Review Considerations

As applicable for the project proposed, reviewers will
consider each of the following items, but will not give scores for these items,
and should not consider them in providing an overall impact/priority score.

Applications from Foreign
Organizations

Reviewers will assess whether the project presents
special opportunities for furthering research programs through the use of
unusual talent, resources, populations, or environmental conditions that exist
in other countries and either are not readily available in the United States or
augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in
this section of the application, including 1) the Select Agent(s) to be used in
the proposed research, 2) the registration status of all entities where Select
Agent(s) will be used, 3) the procedures that will be used to monitor possession
use and transfer of Select Agent(s), and 4) plans for appropriate biosafety,
biocontainment, and security of the Select Agent(s).

Reviewers will consider whether the budget and the
requested period of support are fully justified and reasonable in relation to
the proposed research.

2. Review and Selection
Process

Applications will be evaluated for scientific and technical
merit by (an) appropriate Scientific Review Group(s) convened by NIMH, in accordance with NIH peer
review policy and procedures, using the stated review
criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

May undergo a selection process in which only those applications
deemed to have the highest scientific and technical merit (generally the top
half of applications under review), will be discussed and assigned an overall impact/priority
score.

Will receive a written critique.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds
with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of
review by the appropriate National Advisory Council or Board.

The following will be considered in making funding
decisions:

Scientific and technical merit of the proposed project as
determined by scientific peer review.

Availability of funds.

Relevance of the proposed project to program priorities.

Compliance with resource sharing policies.

3. Anticipated Announcement
and Award Dates

After the peer review of the application is completed, the
PD/PI will be able to access his or her Summary Statement (written critique)
via the eRA
Commons.

If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH Grants
Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided
to the applicant organization for successful applications. The NoA signed by
the grants management officer is the authorizing document and will be sent via
email to the grantee business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection
of an application for award is not an authorization to begin performance. Any
costs incurred before receipt of the NoA are at the recipient's risk. These
costs may be reimbursed only to the extent considered allowable pre-award costs.

A final progress report, invention
statement, and Financial Status Report are required when an award is
relinquished when a recipient changes institutions or when an award is
terminated.

The Federal Funding Accountability and Transparency Act of
2006 (Transparency Act), includes a requirement for awardees of Federal grants
to report information about first-tier subawards and executive compensation
under Federal assistance awards issued in FY2011 or later. All awardees of
applicable NIH grants and cooperative agreements are required to report to
the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants
Policy Statement for additional information on this reporting requirement.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity
and welcome the opportunity to answer questions from potential applicants.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and
under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.